Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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This study was designed to assess a protective effect of palmitoylethanolamide (PEA) in the development of inflammation after ischemia-reperfusion injury of the kidney. Moreover, to suggest a possible mechanism, renal ischemia-reperfusion was performed in mice with targeted disruption of peroxisome proliferator-activated receptor α (PPAR-α) gene (PPAR-αKO) to explain whether the observed PEA effect was dependent on PPAR-α pathway. Peroxisome proliferator-activated receptor-αKO and littermate wild-type controls (PPAR-αWT) were subjected to bilateral renal artery occlusion (30 min) and reperfusion (6 h) and received PEA (10 mg/kg i.p.) 15 min before release of clamps. ⋯ In vivo, PEA administration during ischemia significantly reduced the increase in (i) creatinine, γ-glutamyl transferase, aspartate aminotransferase; (ii) nuclear translocation of nuclear factor κB p65; (iii) kidney myeloperoxidase activity and malondialdehyde levels; (iv) nitrotyrosine, PAR, and adhesion molecules expression; (v) the infiltration and activation of mast cells; and (vi) apoptosis. Our results clearly demonstrate that PEA significantly attenuated the degree of renal dysfunction, injury, and inflammation caused by ischemia-reperfusion injury. Moreover, the positive effects of PEA were at least in part dependent on PPAR-α pathway.
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The mechanisms involved in sepsis-induced acute kidney injury (AKI) are unknown. We investigated the role of nitrosative stress in sepsis-induced AKI by studying the effects of manganese (III) tetrakis-(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP), a peroxynitrite decomposition catalyst, and aminoguanidine (AG), a selective nitric oxide synthase 2 (NOS2) inhibitor and peroxynitrite scavenger, on kidney function of rats subjected to cecal ligation and puncture (CLP). Sprague-Dawley rats (weighing 350 [SD, 50] g) were treated with MnTMPyP (6 mg/kg i.p.) or AG (50 mg/kg i.p.) at t = 12 and 24 h after CLP or sham procedure. ⋯ The sepsis-induced (i) decreased urine output and creatinine clearance and increased fractional excretion of sodium and urinary neutrophil gelatinase-associated lipocalin concentration, (ii) increased protein nitration and NOS2 protein, and (iii) NOS1 and NOS2 upregulation were all significantly attenuated by treatment with MnTMPyP or AG. Nitrated proteins in renal tissue from CLP animals (matrix-assisted laser desorption ionization time-of-flight mass spectrometry) were glutamate dehydrogenase, methylmalonate-semialdehyde dehydrogenase, and aldehyde dehydrogenase, mitochondrial proteins involved in energy metabolism or antioxidant defense. Nitro-oxidative stress is involved in sepsis-induced AKI, and protein nitration seems to be one mechanism involved.
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Aspiration of hydrochloric acid (HCl)-containing gastric juice leads to acute lung injury (ALI) and hypoxemic respiratory failure due to an exuberant inflammatory response associated with pulmonary edema from increased vascular and epithelial permeability. The aim of this study was to determine the role and signaling mechanisms of tumor necrosis factor α (TNF-α) in experimental ALI from HCl aspiration using a combination of genetic animal models and pharmacologic inhibition strategies. To this end, HCl was instilled intratracheally to mice, followed by respiratory system elastance measurement, bronchoalveolar lavage, and lung tissue harvesting 24 h after injection. ⋯ Hydrochloric acid induced a 6-fold increase in apoptotic, caspase 3-positive cells in lung sections from wild-type mice, which was abrogated in mice lacking TNF-α receptor I. In immunoblotting and immunohistochemistry studies, HCl stimulated signaling via p44/42 and c-Jun N-terminal kinase, which was blocked in TNF-α receptor I knockout mice. In conclusion, ALI induced by HCl requires TNF-α receptor I function and associates with activation of downstream proinflammatory signaling pathways p44/42 and c-Jun N-terminal kinase.
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STAT1 (signal transducer and activator of transcription 1) is a member of the JAK-STAT signaling family and plays a key role in facilitating gene transcription in response to activation of the types I and II interferon (IFN) receptors. TYK2 is essential for type I, but not type II, IFN-induced STAT1 activation. Previous studies show that STAT1-deficient mice are resistant to endotoxin-induced shock. ⋯ However, CLP-induced hypothermia and systemic interleukin 6 and CXCL10 production were significantly attenuated in TYK2-deficient mice. These results indicate that STAT1 activation is an important factor in the pathogenesis of CLP-induced septic shock and is associated with the development of systemic inflammation and organ injury. TYK2 activation also appears to contribute to CLP-induced inflammation, but to a lesser extent than STAT1.
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We have previously demonstrated survival benefit to induced hypothermia in a porcine model of controlled hemorrhagic shock simulating an associated delay to definitive care. In the current study, we wished to evaluate the effects of environmental hypothermia in a porcine model of hemorrhagic shock with the addition of polytrauma. Sixteen pigs were randomized to normothermic (39°C, n = 7) or hypothermic (34°C, n = 9) groups. ⋯ Markers of organ injury were elevated in the hypothermia group at 24 h after injury but were identical between groups at the end of the experimental protocol (48 h after injury). There were no noted differences in neurologic function between the two groups. Environmental hypothermia in a model of polytrauma and hemorrhagic shock was not associated with worse outcomes.